Acute lung injury (ALI) is a condition of acute respiratory failure resulting from acute pulmonary inflammation. The airway epithelium provides a complex physical and biochemical barrier to inhaled particles, allergens, and environmental toxins and thus plays a vital role in host defense. Disruption of epithelial integrity is a major contributor to increased permeability and alveolar flooding with protein-rich edema fluid, a hallmark of ALI. However, understanding of the responses of the pulmonary epithelium to injury remains incomplete. E-cadherin-modulated adhesion junction plays a critical role since the formation of adhesion junction subsequently leads to the formation of other cell junctions. Lipopolysaccharide (LPS)-induced lung injury is a very useful experimental model for the investigation and characterization of immunopathogenic changes and mechanisms in ALI. We and others have found that cytoplasmic mislocalization of E-cadherin in pulmonary epithelium induces epithelial shedding and increases pulmonary epithelial permeability in a LPS-induced murine model of ALI and in primary cultured pulmonary epithelial cells. Also, several studies from ours and others have indicated an association between E-cadherin and tyrosine kinase receptor, such as c-Met tyrosine kinase, suggesting a complex molecular mechanisms of regulation of E-cadherin localization in epithelial cells. We recently reported that lysophosphatidic acid (LPA), a bioactive phospholipid growth factor released from activated platelets, enhances innate immunity and attenuates adaptive immunity via increasing IL-8, PGE2, and IL-13R alpha2 secretion in human bronchial epithelial cells (HBEpCs). However, molecular mechanisms of pulmonary epithelial barrier function are poorly defined and in this proposal it is hypothesized that "LPA post-treatment protects against pulmonary epithelial barrier dysfunction caused by LPS through cross-talk between LPA-Rs and c-Met resulting in enhanced E-cadherin accumulation at cell-cell junctions". The following Specific Aims will address the role and regulation of LPA-mediated barrier function in respiratory epithelium using primary human bronchial epithelial cells, alveolar type II epithelial cells, alveolar type II cell line and a murine model of ALI.
Specific aim #1 will define the protective role of LPA in LPS-induced epithelial barrier dysfunction via restoring E-cadherin accumulation at cell-cell junctions.
Specific aim #2 will characterize role of the cross-talk between G-protein-coupled LPA receptors and c-Met receptor tyrosine kinase in LPA-mediated c-Met and E-cadherin redistribution to cell-cell junctions and LPA attenuation of LPS mediated pulmonary epithelial barrier dysfunction.
Specific aim #3 will characterize the role of LPA posttreatment in protecting against LPS-induced lung injury in mice. These studies will identify the molecular mechanisms linking the LPA signaling pathways involving LPA receptors to the pulmonary epithelium barrier function, which is critical to the development of new therapies directed at ameliorating lung inflammatory diseases.

Public Health Relevance

Acute lung injury (ALI) is a cause of acute respiratory failure resulting from acute pulmonary inflammation. The pulmonary epithelium provides a complex physical and biochemical barrier to inhaled particles, allergens, and environmental toxins and thus plays a vital role in host defense. These studies will identify the molecular mechanisms linking the lysophophatidic acid (LPA) and LPA receptors to maintenance of normal pulmonary epithelium barrier function, which is critical in developing novel therapies directed at ameliorating lung inflammatory diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL091916-04
Application #
8303410
Study Section
Special Emphasis Panel (ZRG1-RES-B (02))
Program Officer
Noel, Patricia
Project Start
2009-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$476,209
Indirect Cost
$155,482
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Nan, Ling; Wei, Jianxin; Jacko, Anastasia M et al. (2016) Cross-talk between lysophosphatidic acid receptor 1 and tropomyosin receptor kinase A promotes lung epithelial cell migration. Biochim Biophys Acta 1863:229-35
Zhao, Jing; Wei, Jianxin; Weathington, Nathaniel et al. (2015) Lysophosphatidic acid receptor 1 antagonist ki16425 blunts abdominal and systemic inflammation in a mouse model of peritoneal sepsis. Transl Res 166:80-8
Zhao, Jing; Wei, Jianxin; Bowser, Rachel K et al. (2015) Focal adhesion kinase-mediated activation of glycogen synthase kinase 3β regulates IL-33 receptor internalization and IL-33 signaling. J Immunol 194:795-802
Zhao, Jing; Zhao, Yutong (2015) Interleukin-33 and its Receptor in Pulmonary Inflammatory Diseases. Crit Rev Immunol 35:451-61
Liu, Y; Lear, T; Zhao, Y et al. (2015) F-box protein Fbxl18 mediates polyubiquitylation and proteasomal degradation of the pro-apoptotic SCF subunit Fbxl7. Cell Death Dis 6:e1630
Lendermon, Elizabeth A; Dodd-o, Jeffrey M; Coon, Tiffany A et al. (2015) CD8(+)IL-17(+) T Cells Mediate Neutrophilic Airway Obliteration in T-bet-Deficient Mouse Lung Allograft Recipients. Am J Respir Cell Mol Biol 52:622-33
Zhao, Jing; Wei, Jianxin; Bowser, Rachel K et al. (2014) Molecular regulation of lysophosphatidic acid receptor 1 trafficking to the cell surface. Cell Signal 26:2406-11
Dong, Su; Zhao, Jing; Wei, Jianxin et al. (2014) F-box protein complex FBXL19 regulates TGFβ1-induced E-cadherin down-regulation by mediating Rac3 ubiquitination and degradation. Mol Cancer 13:76
Mialki, Rachel K; Zhao, Jing; Wei, Jianxin et al. (2013) Overexpression of USP14 protease reduces I-κB protein levels and increases cytokine release in lung epithelial cells. J Biol Chem 288:15437-41
Zhao, Yutong; Natarajan, Viswanathan (2013) Lysophosphatidic acid (LPA) and its receptors: role in airway inflammation and remodeling. Biochim Biophys Acta 1831:86-92

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